Clinical evidence has convincingly shown that the BRAF inhibitors (BRAFi) like vemurafenib induce objective tumor regression in >50% of patients with metastatic melanoma that bear the V600E BRAF mutation. However, the tumor regressions are infrequently complete and disease progression occurs at a median of 6-7 months of treatment. Multiple mechanism(s) have been found to support the intrinsic and acquired resistance of melanoma cells to BRAFi and represent major limitations to the use of BRAFi as a single agent in patients with advanced melanoma. Therefore, it is now critical to define combinatorial strategies to eradicate BRAFi sensitive and resistant melanoma cells. In this proposal we will test the hypothesis that BRAFi (vemurafenib) enhances the therapeutic efficacy of IFN?-2b in patients with metastatic melanoma. This hypothesis stems from our novel findings that BRAFi: 1) enhances the sensitivity of melanoma cells to IFN?-mediated anti-proliferative and proapoptotic activity; 2) increases T cell-mediated immune responses to melanoma cells by upregulating tumor antigen presentation and downregulating the expression of inhibitory receptor ligand by melanoma cells and; 3) prolongs the survival of melanoma bearing mice. These findings reflect an increased IFN?-2b sensitivity of melanoma cells harboring BRAF mutations upon treatment with BRAFi. To assess the clinical significance of our experimental data, the proposed Specific Aims will test the following hypotheses: 1) The administration of BRAFi and IFN?-2b to patients with metastatic melanoma is safe, non toxic and immunogenic; 2) The administration of BRAFi enhances the antiproliferative and proapoptotic activity of the of IFN?-2b as well as its ability to upregulate the expression of HLA class I APM component expression by melanoma cells and; 3) The administration of BRAFi and IFN?-2b increases tumor antigen (TA)-specific T cell expansion and function in the tumor microenvironment. The information derived from the outlined studies will conthbute to determine the therapeutic relevance of the BRAFi/IFN?-2b combination and the molecular mechanisms underlying its therapeutic effects.